This proposal seeks to examine gene-environment interactions that contribute to the development of PTSD in 960 persons selected from a well-characterized sample of 2750 men and women in the New York metropolitan area, exposed to the World Trade Center attacks. This cohort was initially recruited six months after September 11th, has been followed longitudinally for the purpose of determining mental health consequences resulting from this event, and is sufficiently large enough to undertake a comprehensive investigation of risk factors for this disorder. We will examine clinical and neuroendocrine measures previously hypothesized or demonstrated to be associated with risk for PTSD, related to alterations in cortisol signaling. Since genetic factors contribute to the function of this biological system, we will examine polymorphisms of several genes related to glucocorticoid activity, as well as peptidergic and monoaminergic neurotransmission implicated in PTSD pathophysiology. To determine the involvement of other relevant genes, we will examine expression profiles using microarray techniques and quantitative polymerase chain reaction. The subset of genes that are validated will also be genotyped for association with PTSD. Additionally, based on recent evidence for non-genetic intergenerational transmission of PTSD and cortisol alterations associated with PTSD (i.e., from trauma-exposed parents with PTSD to their offspring), we will examine stable individual differences in gene activity that are subject to 'programming' by experience via epigenetic mechanisms (e.g., DNA methylation). These studies will focus on specific promoter regions of the glucocorticoid receptor (GR) in lymphocytes, a tissue demonstrated to be more responsive to glucocorticoids in PTSD. It will therefore be possible to associate epigenetic alterations in DNA methylation at GR promoter sites with" genetic and non-genetic risk factors, and their interaction with trauma severity, towards the aim of understanding the simple, but as yet unanswered question of the role of trauma in the development of PTSD, and the even more complex one of why some persons develop PTSD following trauma exposure while others do not. The coincidence of this unique and representative cohort, together with the expertise reflected in this multi-institutional team, will provide unambiguous information concerning the molecular- genetic basis of PTSD, PTSD vulnerability, and stress resistance. Relevance to Public Health: There is a major gap in knowledge regarding why only some exposed to trauma develop PTSD, while the majority do not. This gap results from an over-emphasis on PTSD as a response to an event and an under-emphasis on differences in genetic or early environmental influences that make some more vulnerable. The development of models of prevention and treatment of PTSD can only occur following an understanding of individual risk factors and their interactions with event exposure.